Halogen-pregnadienes

ABSTRACT

COMPOUNDS OF THE FORMULA   2-(CL-),3,20-DI(O=),6-F,9-X,11-(R2=),16-(CH3-),   21-R1-PREGNA-1,4-DIENE   WHEREIN R1=FREE, ESTERIFIED OR ETHERIFIED HYDROXYL R2 = (H-),(-OH) OR (H-),(-OOC-CH3) X=H OR F; OR R2 + X REPRESENTS A 9,11-DOUBLE BOND OR A 9B,11B-OXIDO GROUP AND Y=H, FREE OR ESTERIFIED HYDROXYL FOR EXAMPLE $1,4-2-CHLORO-6A,9A-DIFLUORO-16A-METHYL-3,20DIOXO-11B, 17A-DIHYDROXY-21-ACETOXYPREGANADIENE. USE: AS CORTICOID ANALOGOUS AND ANTIPHOLGISTICS.

United States Patent Oflice 3,652,554 HALOGEN-PREGNADIENES Georg Anner, Ludwig Ehmann, and Jaroslav Kalvoda, Basel, Switzerland, assignors to Ciba Corporation, Summit, NJ.

No Drawing. Filed Nov. 15, 1968, Ser. No. 776,270 Claims priority, application Switzerland, Nov. 17, 1967, 16,101/67 Int. Cl. C07c 169/28 US. Cl. 260-23955 12 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula HzRt /\I RF 2 ..-Y

wherein R =free, esterified or etherified hydroxyl H H R or \OH OOCCHa X=H or F; or

R +X represents a 9,11-double bond or a 9,8,l1B-oxido group and Y=H, free or esterified hydroxyl for example A -2-chloro-6a,9a-difluoro-16a-methyl-3,20- dioxol l [5, 17a-dihydroxy-2 l-acetoxypregnadiene.

Use: as corticoid analgous and antiphlogistics.

BACKGROUND OF THE INVENTION The present invention provides new steroids of the pregnane series which are substituted by chlorine in position 2, corresponding to the Formula I CH2RI 3,652,554 Patented Mar. 28, 1972 acids such as n-valeric acid, or trimethylacetic or trifiuoro acetic acid, a caproic acid such as fi-trimethylpropionic acid or diethylacetic acid, oenanthic, caprylic, pelargonic, capric, an undecyclic acid, for example undecylenic acid, lauric, myrstic, palmitic or stearic acids, for example oleic, cyclopropane-, cyclobutane-, cyclopentaneor cyclohexane-carboxylic acid, cyclopropylmethanecarboxylic, cyclobutylmethanecarboxylic, cyclopentylethanecarboxylic, cyclohexylethanecarboxylic, a cyclopentyl-, cyclohexylor phenyl-acetic or propionic acid, benzoic, phenoxyalkanoic acids such as phenoxyacetic, dicarboxylic acids such as succinic, phthalic, quinolic acid, furan-2-carboxylic, 5- tertiary butyl-furan-Z-carboxylic, S-bromo-furan-Z-carboxylic acid, nicotinic or isonicotinic acid, or sulphonic acids such as benzenesulphonic acids or inorganic acids, for example phosphoric or sulphuric acids.

The ester groups may alternatively be derived from ortho'carboxylic acids such as orthoformic, orthoacetic or orthcipropionic acid, and these acids, as well as the abovementioned dicarboxylic acids, may furnish cyclic 17,21- estrs.

As etherified hydroxyl groups there may be specially mentioned those derived from alcohols with 1 to 8 carbon atoms, such as lower aliphatic alkanols, ethanol, methanol, propanol, isopropanol, the butyl or amyl alcohols,

or from araliphatic alcohols, especially from monocyclic' ary'l-lower aliphatic alcohols, such as benzyl alcohol, or from heterocyclic alcohols, such as a-tetrahydropyranol or -furanol.

The new compounds of the above Formula I possess valuable pharmacological properties, inter alia apart from a thymolytic effect and an inhibiting elfect upon the suprarenals especially an antiphlogistic effect as can be shown in animal tests, for example on rats, by the test for foreign bodies in a granuloma. The new compounds may therefore be used as corticosteroid analogues, especially as antiphlogistics. The new compounds are also valuable intermediates for the manufacture of other useful substances, especially compounds that display a pharmacological activity.

Special mention deserves A -2-chloro-6a,9a-difluoro- 16a methyl 3,20 dioxo-l 1B,l7a-dihydroxy-2l-acetoxypre'gnadiene which, for example, on subcutaneous administr'ation of doses of 0.1 to 1.0 mg./kg. to the rat produces a distinct anti-inflammatory effect.

The compounds of the above Formula I are accessible in known manner; more especially, they are obtained when (a) in a compound of the general formula in which R represents a free, esterified or etherified hydroxyl group, R the group or the OOCOHs (III) in which R R X and Y have the same meanings as in Formula I, a double bond is introduced into the 1,2-position in known manner; or

(d) in a compound of the general formula (V) CH R in which R and Y have the same meanings as in Formula I, an 11,8- or Ila-hydroxyl group is introduced in known manner and from the resulting 116- or lla-hydroxy compound water is eliminated, in the given case with formation of a 9,1l-double bond, and, if desired, in a resulting compound, in known manner, free hydroxyl groups are esterified and/or the 21-hydroxyl group is etherified and/or esterified or etherified hydroxyl groups are converted into free hydroxyl groups.

The addition of chlorine onto the 1,2-double bond according to method (a) is carried out in known manner; for example, the chlorination is performed in an inert solvent, such as dioxane, in the presence of a carboxylic acid, for example propionic acid, at a low temperature in the dark. The elimination of hydrogen chloride from the 1,2-dichlor compounds is achieved by treatment with a base, preferably a tertiary organic nitrogen base, for example triethylamine, pyridine or collidine.

For the hypobromination according to method (b), for example, N-bromosuccinimide is used, preferably in the presence of perchloric acid. The dehydrobromination of the resulting bromohydrin to furnish the 9y3,llfi-oxido compound with a basic agent is advantageously carried out with an alkali metal acetate, for example sodium acetate, in an aliphatic alcohol, for example methanol or ethanol. The resulting 9 3,ll;8-oxido group is split with hydrogen fluoride in the known manner, using anhydrous hydrogen fluoride, if desired in an inert solvent such as chloroform, tetrahydrofuran or especially dimethylformamide, or aqueous hydrofluoric acid. It is also possible to use hydrogen fluoride donors, for example the salts of this acid with a tertiary organic base, for example pyridine or a derivative of hydrofluoric acid. A particularly favourable process has been described in USA. specification 3,211,758, where hydrofluoric acid in the form of an adduct with a carbamic acid or thiocarbamic acid, especially with urea, is used.

To introduce a double bond into a compound of the Formula IV by the method (c) a known chemical or microbiological dehydragenating method is used. From among the chemical methods there may be mentioned, for example, the dehydrogenation by means of selenium dioxide or selenious acid, preferably in a tertiary aliphatic alcohol such as tertiary butanol or tertiary amyl alcohol, or with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in boiling benzene or dioxan.

For the microbiological dehydrogenation there are used, for example, microorganisms of the species Gorynebacterium simplex, Septomyxa afiinis or Didymella lycopersici or enzymes isolated therefrom and freed from the mycelium.

The introduction of a hydroxyl group in position 11,6 by method (d) is likewise performed microbiologically, using the microorganisms described in the literature, especially those of the genus Curvularia, for example Curvularia lunata or Curvularia pallesceus.

For introducing an Ila-hydroxyl group there are used, for example, microorganisms of the order Mucorales, especially of the family Mucoraceae, for example of the genus Rhizopus or Cunninghamella, especially Rhizopus nz'cricans or those of the genus Aspergillus, for example Aspergillus niger or Aspergillus ochraceus.

The dehydrating agent used in the manufacture of the compounds of the Formula III from the corresponding or ll 8-hydroxy compounds saturated in the 9,11- position by elimination of water may be, for example, phosphorus oxychloride in pyridine, or an N-halogenamide or N-halogenimide, for example N-bromosuccinimide and sulphur dioxide under anhydrous conditions, preferably in pyridine.

If desired, the present invention includes the esterification of the free hydroxyl groups in positions 17 and 21. Both 17w or 21-monoesters and 17u,2l-diesters may be manufactured. To manufacture the 21-monoesters the 2l-hydroxy compounds are treated in known manner with reactive functional carboxylic acid derivatives, preferably with those of the above-mentioned acids, for example with an acid anhydride or an acid halide, for instance in a tertiary base such as pyridine.

A free hydroxyl group in position 175; may be selectively esterified in known manner; for example: The 2l-diester is prepared by acylation with a carboxylic acid anhydride, for instance acetic anhydride, with addition of a strong acid, especially an aromatic sulphonic acid, such as p-toluenesulphonic acid, as catalyst, and the 21- ester group is then hydrolyzed under mild conditions, using for instance a solution of an alkali metal carbonate or bicarbonate in an aqueous aliphatic alcohol, such as methanol or ethanol.

l7a-monoesters are also accessible by the following known route: When a compound of the Formula I, that contains free hydroxyl groups in positions 170: and 21, is reacted with an orthoester of the type R'C(OR") (where R represents a hydrogen atom or an alkyl radical and R" an alkyl radical) in the presence of a strong acid, for example p-toluenesulphonic acid, as catalyst in an inert solvent, for example benzene, a cyclic l7a,2lortho-ester is obtained. By hydrolyzing with a weak organic acid, for example, oxalic acid, the 21-ester bond is then selectively hydrolyzed and l7u-monoester is obtained.

The present process includes, if desired, also the etherification of a free hydroxyl group in position 21 in known manner, preferably with a reactive derivative of one of the afore-mentioned alcohols. For example, by using dihydropyran in a solvent that is inert to the reaction, for example tetrahydrofuran, diethyl ether or chloroform, in the presence of phosphorus oxychloride, the 21-tetrahydropyranyl ether is obtained.

The compounds of the above Formulae II to V to be used as starting materials are known or can be prepared in known manner.

The invention includes also any variant of the process in which an intermediate obtained at any stage is used as starting material and any remaining step/steps is/are carried out or the process is discontinued at any stage thereof, or in which a starting material is formed under the reaction conditions.

The present invention is also concerned with the manufacture of pharmaceutical preparations for use in human and veterinary medicine containing the new pharmacologically active substances described above as active ingredients in conjunction or admixture with a pharmaceutical excipient. Suitable excipients are organic or inorganic substances suitable for enteral, for example oral, parenteral or local administration. Suitable excipients are substances that do not react with the new compounds, for example water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, white petroleum jelly, cholesterol or other known medicinal excipients. The pharmaceutical preparations may be in solid form, for example tablets, dragees or capsules, or in liquid or semiliquid form, solutions, suspensions, emulsions, ointments or creams. These pharamceutical preparations may be sterilized and/or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or butters. They may also contain further therapeutically valuable substances. The new compounds may also be used as starting materials for the manufacture of other valuable compounds.

The compounds of this invention may also be used as additives to animal fodders.

The following examples illustrate the invention.

EXAMPLE 1 30.0 grams of A 60t-fll10IO-160t-I116thyl-118,1706-(11- hydroxy 21 acetoxy 3,20-dioxopregnadiene [paramethasone acetate] are dissolved in 1500 ml. of dioxane. The solution is cooled until dioxane begins to crystallize, then 150 ml. of a solution of 84 g. of chlorine in 1 litre of propionic acid are tipped in and the mixture is kept for 2 days at to C. in the dark. The reaction solution is then poured into litres of water, extracted with 4X1 litre of methylenechloride and the extracts are washed successively with water, saturated aqueous sodium bicarbonate solution and once more with water. The washed, combined extracts are dried over sodium-sulphate, filtered and completely evaporated under vacuum at a bath temperature of 30 to 35 C., to yield 48.2 g. of .A -6a-fluoro- 1,2 dichloro 16a methyl 115,175 dihydroxy-21- acetoxy-3,20-dioxopregnene. [a] +57 (c.=0.9% in dioxane). A in reactified alcohol 250 mg (e=10,500). The dichloride is instable and decomposes when left to itself at room temperature.

EXAMPLE 2 A solution of the resulting 48.2 g. of A -6u-fiuoro-1,2- dichloro 16a methyl 1113,1705 dihydroxy 21 acetoxy-3,2 0-dioxopregnene in /2 litre of pyridine is kept for hours at room temperature, during which its colour gradually turns from pink to yellowish brown. The reaction solution is then poured into a mixture of 3 kg. of ice, 10 litres of water and 2 litres of concentrated hydrochloric acid. The whole is extracted with 5X1 litre of methylenechloride and the extracts are washed successively with water, saturated aqueous sodium bicarbonate solution and once more with water; the extracts are then combined, dried over sodium sulphate, filtered and com pletely evaporated under vacuum. For purification the residue is mixed with a small quantity of active carbon and recrystallized from methanol, to yield 21.0 g. of A 6 6a fiuoro 2 chloro 16oz methyl 116,17 dihydroxy-2l-acetoxy-3,20-dioxopregnadiene melting at 232- 233 C. [u] =+55 (c.=1% in dioxane. Amax, in ethanol 251 m (e=14,700).

The infrared spectrum Nujol) displays absorption bands, inter alia, at 2.76, 2.86, 5.71, 5.77, 6.00, 6.09, 8.14, 9.41, 9.60, 9.92 and 10.87

EXAMPLE 3 While stirring a solution of 32.4 g. of A -6a-fluoro-2- chloro 16oz methyl 115,175: dihydroxy 21 acetoxy- 3,20-dioxopregnadiene in ml. of pyridine under nitrogen a solution of 17.1 g. of N-bromosuccinimide in 285 ml. of pyridine is run in within 10 minutes at 20 to 25 C. The brownish reaction solution is then cooled to 12 to l3 C. Then, while providing a permanent, successively increased cooling at 12 C. and finally at 20 C., within 50 to 70 minutes, a moderate current of sulphur dioxide is introduced until active bromine can no longer be detected in the reaction solution, and the introduction of sulphur dioxide is then continued for 15 to 20 minutes. The cooling is then discontinued and within 1 /2 to 2 hours a total of 2.25 litres of water is run into the brown, partially crystalline reaction mixture at first slowly and then more rapidly, during which the temperature gradually rises to 20 to 25 C. and the reaction product crystallizes out slowly from the solution which temporarily turns clear. The product is suctioned off, washed with 1 litre of water and dried under vacuum at 50 to 60 C. Yield: 29.1 g. of A -6u-fluoro-2-chloro-1-6amethyl 17m hydroxy 21 acetoxy 3,20 dioxopregnatriene melting at 128 to 132 C. [a] =8 (c.=1.0% in chloroform), k in rectified alcohol 247 m (e=15,900).

EXAMPLE 4 While stirring a solution of 5.00 g. of A -2-chloro- 60c fluoro 16cc methyl 3,20 dioxo 11;9,17a dihydroxy-2l-acetoxy-pregnatriene in 60 ml. of absolute dioxane and 7.5 ml. of 0.5 N-perchloric acid in the dark at 18 to 20 C., a solution of 2.34 g. of N-bromoacetamide in 40 ml. of absolute dioxane is dropped in within 15 minutes and the whole is then stirred for 4 hours under nitrogen in the dark at room temperature. Then, Within 10 minutes, 15 m1. of 10% sodium thiosulphate solution (loss of colour) and then within .15 minutes 100 ml. of Water are dropped in at 18 to 20 C. A solution of 1.5 g. of sodium hydroxide in 15 ml. of water and 10 ml. of methanol are added at about 20 C. and the reddish mixture is stirred for 1 hour under nitrogen at room temperature. At about 10 C., within 30 minutes, 400 ml. of water are dropped in; the precipitate is suctioned 01f, rinsed with water, dissolved in methylenechloride, the solution dried over sodium sulphate and evaporated to dryness under a water-jet 'vacuum. The yellow foam (4.64 g.) is sprinkled with ether and recrystallized from a mixture of methylenechloride+methanol+ether, to furnish 3.1 8 g. of pure A -2-chloro-6a-fiuoro-16a-methyl- 9B,11fl-oxido-3,2=0-dioxo :,21 dihydroxypregnadiene melting at 200 to 202 C. [a] =-10:l (c.=0.964). Ultraviolet spectrum: A 254 mu (e=15,500).

Infrared spectrum, bands, inter alia, at 2.77, 2.85, 5.84, 5.97, 6.03, 6.20, 8.80, 9.37, 9.90, 10.1 0, 10.95 and 11.87

EXAMPLE 5 A solution of 1.80 grams of A -2-chloro-6a-lluoro- 1 60c methyl 95,115 oxido 3,20 dioxo 1705,21- dihydroxypregnadiene in .10 ml. of pyridine and 10 ml. of acetic anhydride is kept for 15 hours at room temperature. The clear, yellow solution is poured into ice Water and stirred for 30 minutes, and then extracted twice with chloroform. The organic phases are successively washed with water, dilute sulphuric acid/ice, water, saturated sodium bicarbonate solution/ ice and with water until the washings run neutral, dried over sodium sulphate and evaporated to dryness under a water-jet vacuum. The resulting yellowish oil (1.89 g.) is sprinkled with ether and redissolved once from methylenechloride-i-ether, to yield 1.23 g. of pure 2l-acetate of the above starting material, melting at 184 C. Ultraviolet spectrum: A =254 mu (e=15,400) [in ethanol]. [a] '-=+5:2 (c. =0.5-80 in chloroform). Infrared spectrum, bands, inter alia, at 2.75, 5.70, 5.75, 5.96, 6.18, 7.25, 8.12, 9.40, 9.93 and 1095 1..

EXAMPLE 6 2.62 grams of the acetate obtained in Example are introduced into a polyethylene vessel containing 60 ml. of urea-hydrogen fluoride adduct (1:1.325) and stirred for 40 hours with exclusion of air by means of a Teflon mag netic stirrer at 3 C. (:l C.). The suspension is stirred into a mixture of 700 g. of ice and 200 ml. of concentrated ammonia and then adjusted with glacial acetic acid to pH 7. The precipitate is suctioned off, rinsed with water, dissolved in chloroform, the solution is dried over sodium sulphate and evaporated to dryness under a water-jet vacuum. The resulting brown crystals (about 2.8 g.) are dissolved in a 4:1-mixture of toluene and ethyl acetate and filtered through 120 g. of silica gel. The fractions which crystallize in a gelatinous form are dissolved with heating in methylenechlorlde, concentrated under atmospheric pressure and a small quantity of ether is added, to yield 1.06 g. of pure A -2-chloro-6a,9a-difiuoro-l6amethyl-3,20-dioxo 11/3,17a dihydroxy-Zl-acetoxypregnadiene melting at (202) 204 C. According to thin-layer chromatography the mother liquor likewise contains 95% of this product. [a] =+48-,i:2 (c.=0.497). Ultraviolet spectrum: A =246 m (e=15,800). Infrared spectrum (Nujol) bands, inter alia, at 2.82, 5.70, 5.76, 6.15, 7.83, 8.74, 9.37, 9.91, 10.50, 10.95 and 1125 EXAMPLE 7 9.4 g. of A -6a-fluoro-2-chloro-16u-methyl-11 3,170:- dihydroxy-2l-aoetoxy-3,20-dioxopregnadiene are dissolved in 400 ml. of methanol by heating to the boil while introducing nitrogen. The resulting solution is cooled under nitrogen to 1-3 C. and, within -30 minutes, a solution of 1.7 g. of sodium bicarbonate in 50 ml. of water is added dropwise. Stirring of the reaction solution is continued overnight at 13 C. under nitrogen, the reaction product crystallizing out gradually. The course of hydrolysis is observed by means of thin layer chromatography on silica gel using toluene+ethyl acetate 1:1 as running agent. After 10-15 hours saponification it is no longer possible to detect any starting material in the reaction solution. The mixture is then poured into 2 litres of water. There follow several extractions with methylene chloride, and the extracts are washed repeatedly with water and dried over sodium sulfate, filtered and evaporated completely. A yield of 7.65 g. of crystalline crude product melting at 175 C. is obtained. The product is pure according to thin-layer chromatography (silica gel, toluene+ ethyl acetate 1:1). For further purification, the crude product which has a slight yellow tint is crystallized from ethyl acetate, and 2.87 g. of A -6ot-fil1O1O-2-Chl0r0-16amethyl-11fi,17a,21-trihydr0xy 3,20-dioxo-pregnadiene of melting point (180 C.) 181-182 C. are obtained.

On concentration of the mother liquor further quantities of the same product are obtained.

EXAMPLE 8 9.0 grams of A -6Ot,90!.-d1fll.l0rO-1GOt-IIICthYl-llfl,170tdihydroxy-Zl-acetoxy 3,20 dioxopregn'adiene (flumethasone acetate) are dissolved in 750 ml. of pure dioxan with the application of heat. After cooling until crystallization of the dioxan sets in, 66 ml. of a solution of 36 g. of chlorine in 500 ml. of pure propionic acid are added all at once and the whole is allowed to stand in the dark at 0-5 C. for 7 days. The reaction solution is poured into 3 litres of iced water. The batch is extracted with 3 x 5 00 ml. of methylene chloride and the extracts washed successively with water, saturated aqueous sodium bicarbonate solution, and water. The extracts are then combined and dried over sodium sulfate, filtered, evaporated completely under reduced pressure at a bath temperature of 30-35 C. There are obtained 11.7 g. of A -6a,9a-difiuoro,1,2-dichloro-16a-methyl 115,170; dihydroxy-21- acetoxy-3,20-dioxo-pregnene. The IR spectrum (methylene chloride) exhibits absorption bands inter alia at 2.80, 3.95, 5.75, 5.95, 7.25, 8.20, 8.85, 9.45, 9.60, 10.05 and 1135a.

The dichloride is unstable and decomposes when allowed to stand at room temperature.

11.7 g. of A -6a,9a-difiuoro-1,2-dichloro-l6a-methyll1,8,17u-dihydroxy-21-acetoxy-3,20-dioxopregnene are dissolved in 150 ml. of pure pyridine and the solution allowed to stand at room temperature for 24 hours, when the color gradually changes from pink to yellow to brown. The reaction solution is then poured into 1 litre of icecooled normal hydrochloric acid. The batch is then extracted with 5x 250 ml. of methylene chloride and the extracts are washed successively and repeatedly with icecooled, normal hydrochloric acid, water, ice-cooled, saturated sodium bicarbonate solution, and water. The extracts are then combined and dried over sodium sulfate, filtered, and completely evaporated under reduced pressure. The resulting, partly crystalline crude product (10 g.) is chromatographed on 750 g. of silica gel (diameter of column, 6 cm.), elution being performed with toluene+ethyl acetate 95:5, then 90:10, and finally :20. From the first runnings (fractions 69-80) there is obtained on concentration, 0.7 g. of A -6a,9a-difluoro-2- chloro-16a-methyl-17rx-hydroxy 116,21 diacetoxy-3,20- dioxo-pregnadiene of melting point (240 C.) 246-250 C.; [a] +90 (c.=1% in dioxan) and A (rectified alcohol) 245 m (e=14,600). The fractions 86-115 are jointly evaporated completely and the residue recrystallized from rectified alcohol to obtain 2.4 g. of A -611,9- difluoro-Z-chloro-16a-methyl 113,170: dihydroxy-21- acetoxy-3,20-dioxo-pregnadiene which melts between 200 and 210 0.; [a] +61 (c.=1% in dioxane and A (rectified alcohol) 246 m e==16,100). When the mother liquors are concentrated, further quantities of the same compound are obtained.

EXAMPLE 9 18.0 grams of A -6a,9a-difluoro-16a-methyl-115,170:- dihydroxy 21 trimethylacetoxy-3,ZO-diOXo-pregnadiene are dissolved in 1500 ml. of pure dioxan. The solution is cooled until crystallization of the dioxan sets in, and then 90 ml. of a solution of 72 g. of chlorine in 1000 ml. of propionic acid are added all at once, and the whole allowed to stand in the dark at 0-5 C. for 7 days. The batch is worked up as described in Example 1, and 22.7 g. of A 6a,9u-difluoro-1,2-dichloro-16a-methy1-11,3,17a-dihydroxy 21 trimethylacetoxy-3,20dioxo-pregnene obtained which melt at 200 C. with decomposition.

The 22.7 g. of this product are covered with 300 ml. of pure, dry pyridine, a clear, pale-brown solution forming immediately. The solution is allowed to stand at room temperature for 2 days and then worked up as described in Example 2. The resulting brownish, crystalline crude product (20.9 g.) is chromatographed on 2300 g. of silica gel (diameter of column, 12 cm.) with toluene+ethyl acetate :5. The first runnings are separated (fractions 10- 25), and the fractions 38-61 then evaporated and the residue recrystallized from ethyl acetate. There are obtained 4.68 g. of A 60:,90: difiuoro 2-chloro-16a-methyl- 11;3,17u dihydroxy 21 trimethylacetoxy-3,20-dioxo pregnadiene of melting point (242 C.) 243-244 C.; [m] 20 +58 (c.=0.8% in dioxan) and k (rectified alcohol) 247 my. (e=16,200). When the mother liquor is concentrated, further quantities of utilizable material are obtained.

9 EXAMPLE 1o Pharmaceutical preparation in the form of an ointment for local administration, containing A -2-Ch101'O-6a,9otdifluoro 160: methyl 3,20-dioXo-11B,17a-dihydroxy- ZI-acetoxypregnadiene, consisting of:

A 2 chloro 611,90: difluoro-16u-methyl-3,20-

dioxo-l16,17u-dihydroxy-21-acetoxypregnadiene 0.1

The fats and emulsifiers are fused together, the preservatives dissolved in water and the solution is emulsified in the fat melt at an elevated temperature. After cooling, a suspension of the active ingredient in part of the fat melt is worked into the emulsion and then the perfume is added.

We claim: 1. A compound of the general formula (I) CH2R1 in which R represents a free, esterified or etherified hydroxyl group, R the group H H or the OH 0 o 0 OH;

group, X a hydrogen or fluorine atom or R +X represents a 9,11-double bond or a 95,115-oxido group and Y represents a free or esterified hydroxyl group, each of said esterifiedhydroxyl groups being derived from a carboxylic acid having 1 to 18 carbon atoms and each of said etherified hydroxyl groups being derived from alcohols having 1 to 8 carbon atoms.

2. A compound of the formula as claimed in claim 1, wherein R is a hydroxy group esterified with a carboxylic acid having 1 to 18 carbon atoms, R and Y represent each a hydroxy group and X stands for hydrogen or fluorine.

3. A compound of the formula as claimed in claim 1, wherein R is an acetoxy group, R and Y represent each a hydroxy group and X stands for hydrogen or fluorine.

4. A compound of the formula as claimed in claim 1, wherein R is a hydroxy group esterified with a carboxylic acid having 1 to 18 carbon atoms, Y represents a hydroxy group and R together with X stand for the 9,11 double bond or a 9,8,11,8-0Xid0 group.

5. A compound of the formula as claimed in claim 1, wherein R is the acetoxy group, Y represents a hydroxy group and R together with X stand for the 9,11-double bond or a 9,8,115-oxido group.

6. A compound as claimed in claim 1 and being A -2- chloro L fluoro 16a-methyl-11,6,l7a,21-trihydroxy- 3,20-dioxo-pregnadiene.

7. A compound as claimed in claim 1 and being A -2- chloro 60c fluoro 16a-methyl-11fl,17a,21-trihydroxy- 3,20-dioxo-pregnadiene-2l-acetate.

8. A compound as claimed in claim 1 and being A1I419(11) 2 chloro-6a-fluoro-16a-methyl-17a-hydroxy- 21-acetoXy-3,20-dioxo-pregnatriene.

9. A compound as claimed in claim 1 and being A -2- chloro 60c fluoro-16a-methyl-9,11/8-oxid0-17a-hydroxy- 21-acetoxy-3,20-dioXo-pregnadiene.

10. A compound as claimed in claim 1 and being A 2 chloro 6u,9a difiuoro-16a-methyl-11;8,17a,21-trihydroxy-3,ZO-dioxo-pregnadiene.

11. A compound as claimed in claim 1 and being A- 2 chloro 6a,9a-difluoro-16a-methy1-11B,17a-dihydroxy- 2l-acetoXy-3,20-dioxo-pregnadiene.

12. A compound as claimed in claim 1 and being A 2 chloro 6a,9a difluoro-16a-methyl-11,3,17a-dihydroXy-21-trimethy1acetoXy-3,20-dioXo-pregnadiene.

References Cited UNITED STATES PATENTS 2,865,936 12/ 1950 Schneider et al. 260-397.45 3,499,016 3/1970 Lincoln et al 260397.45 3,152,154 10/1964 Ercoli et al. 260-'397.45 3,232,835 2/1966 Figdor et a1. 167-65 FOREIGN PATENTS 837,107 8/1960 France 260397.45 836,531 8/1960 France 260397.45 837,260 8/1960 France 260397.45 106,332 10/1963 Netherlands 260-397.45 1,150,385 5/1967 Germany.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R.

P0-1050 UNITED STATES PATENT OFFICE EERTIWCATE @F QQEC'HQN Patent No. 3,652,554 Dated Marsh 28, 1972 Inventor) Anner et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 9, the upper right-hand portion of formula (I) should read:

CH R I C=O IIY Signed and sealed this 30th day of January 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents aaa 

